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This uses a clever experimental design to ask whether newborn hippocampal neurons are activated by learning and memory, and if so, how their involvement compares to that of older, established granule cells. The authors find that newborn hippocampal neurons are preferentially activated by spatial learning tasks compared to older granule cells, but that this preferential activation only occurs after the new neurons reach 4-6 weeks of age. This timing is remarkably consistent with previous studies from the Gage lab and others showing that newborn neurons take several weeks to reach their target field and develop synaptic spines, and require up to 5 weeks to become functionally mature.

The preferential activation of this maturing newborn population of neurons suggests that these cells may be especially suited for the acquisition and/or storage of new information. However, the water maze task used to induce learning and memory in this study has been the one test that has consistently shown little impact of treatments designed to inhibit neurogenesis. The lack of effect on water maze performance has been interpreted to suggest that newborn neurons are not required for spatial tasks. The data presented here indicates that, in fact, when this pool of newborn neurons is available, it is preferentially activated over older granule cells during the recall of spatial information.

The apparent contradiction between the blocking experiments and the endogenous activation is intriguing. It may suggest that either treatment used to block neurogenesis in past work (MAM, X-irradiation, and targeted ablation) does not completely suppress the production of new neurons, or that memories created from spatial tasks are especially resilient to degradation of the memory network. Kee et al. suggest yet another consideration based on their findings. Studies designed to inhibit neurogenesis generally test its effect within a few weeks of treatment. As shown by Kee et al., greatest incorporation of newborn neurons into memory networks occurs much later, roughly 4-8 weeks after division. However, this explanation does not account for treatments based on X-irradiation, which are usually delivered several months before behavioral testing, leaving the exact role of newborn neurons in spatial learning unclear.

The role of newborn hippocampal neurons in learning and memory is especially relevant for Alzheimer disease, as several groups have shown decreased neurogenesis in FAD transgenic APP and PS1 mice. Given that Kee et al. show these newborn neurons to be preferentially activated during learning and memory, the diminishment of this population in mouse models for AD may contribute to the cognitive deficits described in many APP and PS1 mice. However, directly linking deficits in neurogenesis with functional decline in Alzheimer disease is a tall order that will require future study.